Predictive testing for neurodegenerative diseases in the age of next-generation sequencing.

The availability and cost of next-generation sequencing (NSG) now allow testing large numbers of genes simultaneously. However, the gold standard for predictive testing has been to test only for a known family mutation or confirmed family disease. The goal of this study was to investigate the psychological impact of predictive testing for autosomal dominant neurodegenerative diseases without a known family mutation using next-generation sequencing panels compared to single-gene testing of a known family mutation. Fourteen individuals from families with a known mutation and 10 individuals with unknown family mutations participated. Participants completed questionnaires on demographics, genetic knowledge, and psychological measures of anxiety, depression, perceived personal control, rumination, and intolerance to uncertainty at baseline and 1 and 6 months after receiving results. Decision regret was measured 1 and 6 months after receiving results. Participants completed a modified Huntington disease genetic testing protocol with genetic counseling and neurological and psychological evaluation. Genetic testing of either the known family mutation or an NGS panel of neurodegenerative disease genes was performed. Semi-structured interviews were performed at 6 months post-results about their experience. Two-sample t tests were performed on data collected at each time point to identify significant between-group differences in demographic variables, baseline psychological scores, and baseline genetic knowledge scores. Within-group change over time was assessed by a mixed-effects model. Results of this study indicate that NGS panels for predictive testing for neurodegenerative disease are safe and beneficial to participants when performed within a modified HD protocol. Though significant differences in psychological outcomes were found, these differences may have been driven by genetic results and baseline psychological differences between individuals within the groups. Participants did not regret their decision to test and were largely pleased with the testing protocol.

Regulation of Laboratory-Developed Tests in Preventive Oncology: Emerging Needs and Opportunities.

Cancer predictive or diagnostic assays, offered as Laboratory-Developed Tests (LDTs), have been subject to regulatory authority and enforcement discretion by the US Food and Drug Administration. Many LDTs enter the market without US Food and Drug Administration or any regulatory review. The Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement Amendments focuses on analytic performance, but has limited oversight of the quality or utility of LDTs, including whether patients have been harmed as a result of their use. Increasingly, LDTs for cancer risk or early detection have been marketed directly to consumers, with many LDT developers depicting these tests, requested by patients but ordered by personal or company-associated physicians, as procedures falling under the practice of medicine. This patchwork of regulation and enforcement uncertainty regarding LDTs and public concerns about accuracy of tests given emergency authorization during the COVID-19 pandemic led to the Verifying Accurate Leading-edge IVCT (in vitro clinical test) Development Act of 2021. This pending federal legislation represents an opportunity to harmonize regulatory policies and address growing concerns over quality, utility, and safety of LDTs for cancer genomics, including tests marketed directly to consumers. We review here questions regarding the potential benefits and harms of some cancer-related LDTs for cancer risk and presymptomatic molecular diagnosis, increasingly marketed to oncologists or directly to the worried well. We offer specific proposals to strengthen oversight of the accuracy and clinical utility of cancer genetic testing to ensure public safety.

Comprehensive analysis of germline drivers in endometrial cancer.

BACKGROUND: We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features. METHODS: Germline assessment of at least 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing from January 1, 2015, to June 30, 2021. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using nonparametric tests. RESULTS: Of 1625 patients with EC, 216 (13%) had gPVs, and 15 patients had 2 gPVs. There were 231 gPVs in 35 genes (75 [32%] high penetrance; 39 [17%] moderate penetrance; and 117 [51%] low, recessive, or uncertain penetrance). Compared with those without gPVs, patients with gPVs were younger (P = .002), more often White (P = .009), and less obese (P = .025) and had differences in distribution of tumor histology (P = .017) and molecular subtype (P < .001). Among 231 gPVs, 74 (32%) exhibited biallelic inactivation within tumors. For high-penetrance gPVs, 63% (47 of 75) of ECs had biallelic alterations, primarily affecting mismatch repair (MMR) and homologous recombination related genes, including BRCA1,BRCA2, RAD51D, and PALB2. Biallelic inactivation varied across molecular subtypes with highest rates in microsatellite instability-high (MSI-H) or copy-number (CN)-high subtypes (3 of 12 [25%] POLE, 30 of 77 [39%] MSI-H, 27 of 60 [45%] CN-high, 9 of 57 [16%] CN-low; P < .001). CONCLUSIONS: Of unselected patients with EC, 13% had gPVs, with 63% of gPVs in high-penetrance genes (MMR and homologous recombination) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention.

Denosumab-Induced Hypocalcemia after Billroth II Gastric Bypass Surgery.

Hypocalcemia is a known risk following bariatric surgery and can contribute to the development of osteoporosis. Osteoporosis is commonly treated with denosumab, though denosumab can exacerbate underlying abnormalities in calcium homeostasis. We present the case of a 59-year-old female with severe hypocalcemia who had been treated with denosumab for osteoporosis three months before and had Billroth II gastric bypass surgery 15 years before, for bariatric purposes. Intravenous calcium supplementation was used to correct the initial electrolyte abnormality, and the patient was able to maintain appropriate calcium levels on high doses of oral calcium before discharge. Denosumab-induced hypocalcemia has been previously reported in patients with predisposing conditions including chronic kidney disease, primary sclerosing cholangitis, Crohn's disease, and a history of sleeve gastrectomy for marginal gastric ulcers. A few cases of hypocalcemia have been reported in patients with a history of bariatric surgery secondary to vitamin D deficiency, but this report is unique in demonstrating denosumab-induced hypocalcemia after bariatric surgery with normal vitamin D levels, suggesting a primary malabsorption of calcium. The risk of severe hypocalcemia should be considered before initiating denosumab to treat osteoporosis in patients with a history of bariatric surgery. If denosumab is initiated, serum calcium levels should be closely monitored, and patients should be educated about the importance of adherence to calcium supplementation.

New therapies for diabetes.

The role of hormones secreted by the gut in maintaining blood glucose homeostasis has recently been recognized. This recognition has led to the emergence of several novel classes of medications--the glucagon-like peptide-1 (GLP-1) agonists and the dipeptidyl peptidase (DPP)-IV inhibitors--that may target a key element of the underlying pathophysiology of type 2 diabetes mellitus (DM). Both GLP-1 agonists and DPP-IV inhibitors may have the ability to expand beta-cell mass. Because the demise of beta-cell mass and function is a critical element in the progression of type 2 DM, these agents may have the potential to reverse the natural history of type 2 DM. However, further studies are needed to confirm both long-term beta-cell preservation and the role of these agents in the management of diabetes.

Relationship between aldosterone and progesterone in the human menstrual cycle.

CONTEXT: Aldosterone levels increase during the luteal phase of the menstrual cycle. Prior studies examining relationships between aldosterone and female sex hormones did not control for sodium balance, a major determinant of aldosterone production. OBJECTIVES: The objectives of this study were 1) to compare aldosterone levels between menstrual phases among cycling women in high- and low-sodium balance; and 2) to examine the relationships between aldosterone and female sex hormones in women and the effects of sex hormones on rat zona glomerulosa (ZG) cell aldosterone production in vitro. SUBJECTS/INTERVENTIONS: Normotensive, premenopausal women were studied in low- and/or high-sodium balance. Urinary aldosterone, basal serum aldosterone, plasma renin activity (PRA), plasma angiotensin II (AngII), and serum aldosterone after AngII infusion were measured. Isolated rat ZG cells were treated with progesterone, estradiol, or both, and aldosterone was measured. RESULTS: In high-sodium balance, urinary aldosterone, basal serum aldosterone, and serum aldosterone response to infused AngII were significantly greater (P < 0.05) in the luteal vs. follicular phase. PRA, AngII, and potassium did not differ. Progesterone directly correlated with urinary aldosterone, basal serum aldosterone, and serum aldosterone response to infused AngII. Estradiol did not significantly correlate with aldosterone. In low-sodium balance, no significant differences in aldosterone levels between phases were found. In vitro, progesterone increased ZG cell aldosterone production (P < 0.01), whereas estradiol had no effect. CONCLUSIONS: In women, urinary and serum aldosterone levels are significantly higher during the luteal phase in high- but not low-sodium balance, whereas PRA and AngII do not differ between phases. Progesterone may directly contribute to increased luteal phase aldosterone production, independent of the renin-angiotensin system.

Durability of the effect of online diabetes training for medical residents on knowledge, confidence, and inpatient glycemia.

BACKGROUND: Inpatient dysglycemia is associated with increased morbidity, mortality and cost. Medical education must not only address knowledge gaps, but also improve clinical care. METHODS: All 129 medicine residents at a large academic medical center were offered a case-based online curriculum on the management of inpatient dysglycemia in the fall of 2009. First-year residents took a 3-h course with 10 modules. Second and third-year residents, who had been educated the prior year, underwent abbreviated training. All residents were offered a 20-min refresher course in the spring of 2009. We assessed resident knowledge, resident confidence, and patient glycemia on two teaching wards before and after the initial intervention, as well as after the refresher course. RESULTS: A total of 117 residents (91%) completed the initial training; 299 analyzed admissions generated 11, 089 blood glucose values and 4799 event blood glucose values. Admissions with target glycemia increased from 19.4% to 33.0% (P = 0.035) by the end of the curriculum. There was a strong downward trend in hyperglycemia from 22.4% to 11.3% (P = 0.055) without increased hypoglycemia. Confidence and knowledge increased significantly among first-time and repeat participants. Residents rated the intervention as highly relevant to their practice and technologically well implemented. CONCLUSION: Optimization of an online curriculum covering the management of inpatient glycemia over the course of 2 years led to significantly more admissions in the target glycemia range. Given its scalability, modularity and applicability, this web-based educational intervention may become the standard curriculum for the management of inpatient glycemia.

Effect of case-based training for medical residents on confidence, knowledge, and management of inpatient glycemia.

OBJECTIVE: To determine whether a brief, case-based educational intervention improves resident confidence, knowledge, and management of glycemia in hospitalized patients. RESEARCH DESIGN AND METHODS: All 116 medical residents at a large academic medical center were offered a case-based curriculum on the management of inpatient glycemia in fall 2008. Residents on ambulatory and elective rotations were taught in small groups, whereas all others underwent online training. All participants were offered a brief online refresher course in spring 2009. We assessed resident confidence across 9 domains of treating inpatient dysglycemia, knowledge based on 4 questions before the course, a 23-part questionnaire after the intervention, and changes in resident behavior as documented in chart abstractions. RESULTS: One hundred eight (93.1%) residents completed initial training, and 102 (87.9%) completed the refresher course. The share of scores indicating that residents felt "somewhat comfortable" or "completely comfortable" treating inpatient dysglycemia increased from 62.5% before the course to 94.3% (P<0.001) after the initial intervention and 92.8% (P<0.001) after the refresher. Knowledge scores improved from 72.2% correct answers to 88.9% (P<0.001) for the 4 questions asked before and after the course. Across all 23 questions posed after the initial course, residents answered 86.1% correctly and maintained a score of 85.5% after the refresher course. Online-trained residents, at 89.7%, outscored their classroom-trained peers (82.3%; P<0.001) after the initial course. Chart abstractions did not show any significant changes in managing glycemia. CONCLUSION: A curriculum on the management of inpatient glycemia was broadly adopted by medical residents at a large academic medical center and led to greater confidence and knowledge among residents. Further expansion to other health care providers and hospitals using a Web-based format and incorporation of updated guidelines is needed to confirm and build on these encouraging results.

Effect of case-based training for medical residents on inpatient glycemia.

OBJECTIVE: To determine whether an educational intervention for medical house staff improves blood glucose (BG) in hospitalized patients. RESEARCH DESIGN AND METHODS: All 116 medicine residents at an academic medical center were assigned to online or classroom training on inpatient dysglycemia in fall 2008. Both groups were offered an online refresher course in spring 2009 addressing gaps in clinical practice identified on chart review. We assessed event BG, the first BG of any 3-h period, on two teaching wards. RESULTS: A total of 108 residents (93.1%) completed the initial training. The primary outcome, median event BG, decreased from 152 mg/dL in August 2008 to 139 mg/dL in December 2008 (P < 0.0001). Prevalence of event BG >200 mg/dL decreased from 25.5 to 22.7% (P = 0.0207), at the expense of more event BGs <70 mg/dL (2.0-3.9%, P = 0.0124). CONCLUSIONS: A curriculum for medicine residents on inpatient glycemia led to lower inpatient BG.